Immune Response to HIV

Cytotoxic T-cells with a wide spectrum of activity may be necessary to detect and destroy memory CD4 T-cells containing inactive reservoir HIV from people who start antiretroviral therapy (ART) during chronic infection, according to research reported in the January 7 edition of Nature. People who start treatment very early, however, may still have non-mutated virus that is susceptible to detection by normal killer T-cells -- and a therapeutic vaccine may help boost immune responses in those treated later.

Researchers have identified broadly neutralizing antibodies targeting variable regions of the HIV-1 envelope that controlled superinfection in a South African woman, according to a report in the March 2, 2014, online edition of Nature. Learning more about such antibodies and how they work may aid the development of preventive or therapeutic HIV vaccines.

Although the body produces antibodies in response to HIV infection, in most people the immune system is not able to control the virus. Some individuals, however, do manage to keep HIV in check, offering insight into what must be done to give other people this ability.

At an HIV community cure workshop preceding the Conference on Retroviruses and Opportunistic Infections (CROI 2014) this week in Boston, Romas Gelezunias from Gilead Sciences described several avenues of HIV cure research, including potent and broadly neutralizing monoclonal antibodies derived from HIV patients he dubbed "elite neutralizers."

Below is an edited excerpt from a press release issued by Wits University describing the Nature study in more detail.

New Research on Potent HIV Antibodies

March 3, 2014 -- The discovery of how a KwaZulu-Natal woman’s body responded to her HIV infection by making potent antibodies (called broadly neutralizing antibodies, because they are able to kill multiple strains of HIV from across the world), was reported today by the CAPRISA consortium of AIDS researchers jointly with scientists from the United States.

The study, published in the scientific journal Nature, describes how the research team found and identified these antibodies in her blood and then duplicated them by cloning the antibodies in the laboratory. The cloned antibodies were then used in a series of experiments in the laboratory to elucidate the pathway followed by her immune system to make these potent antibodies.

The South African researchers in the CAPRISA consortium, which includes scientists from Wits University, the National Institute for Communicable Diseases (NICD) in Johannesburg, the University of KwaZulu-Natal and the University of Cape Town, worked jointly with U.S. partners based at the Vaccine Research Center of the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, and Columbia University in New York, to conduct this research.

"In this new publication, we have been able to isolate a broadly neutralizing antibody from this CAPRISA volunteer and trace its origins to understand exactly how it arose. This could lead to new HIV vaccine strategies that are able to stimulate the rare precursors of these protective antibodies," says Professor Lynn Morris, from the National Health Laboratory Service in the Wits School of Pathology who leads the research team at the NICD.

Professor Salim S. Abdool Karim, leader of the CAPRISA consortium and President of the Medical Research Council, commented, "The new insights gained from this KwaZulu-Natal woman into immune responses against HIV bring hope for future HIV prevention and treatment strategies. This woman, referred to as CAPRISA 256 (abbreviated to CAP256), is doing well on antiretroviral therapy and continues to attend the CAPRISA clinic regularly."

Just over a year ago, the same team of South African researchers reported in Nature Medicine (also part of the Nature group of journals) on their discovery relating to two other KwaZulu-Natal women, that a shift in the position of one sugar molecule on the surface of the virus led to the development of broadly neutralizing antibodies against HIV.

All HIV infected people respond to HIV by making antibodies. In most patients, these antibodies are not able to kill a wide range of HIV -- this is described as a lack of neutralization breadth. However, in a few infected people, they naturally make antibodies that kill (neutralize) many different kinds of HIV (i.e. they are broadly neutralizing antibodies).

"Broadly neutralizing antibodies have some unusual features," says Dr. Penny Moore, from Wits University and one of the lead South African scientists on the study based at the NICD. "The outer covering (envelope) of HIV has a coating of sugars that prevents antibodies from reaching the surface to neutralize the virus. In this patient, we found that her antibodies had 'long arms', which enabled them to reach through the sugar coat that protects HIV." In this study, the researchers found that these antibodies had 'long arms' right at the outset. "We discovered that some HIV antibodies are born with 'long arms', requiring less time and fewer changes to become effective in killing HIV," says Moore.

The identification and successful cloning of these special antibodies enables the researchers to make sufficiently large quantities for further testing, similar to the way a medicine used to prevent or treat HIV would be tested. "Our goal is to test these antibodies, preferably in combination with other broadly neutralizing antibodies, directly in patients with HIV infection or in patients at risk of getting infected," said Karim. "But this will take some time as the team is currently planning animal studies as a first step.

Broadly neutralizing antibodies have previously been shown to be effective in preventing and treating HIV infection in animals, but this has never before been shown in humans." The future studies on animals and humans are being supported by the Strategic Health Innovation Partnerships, a unit of the South African Medical Research Council, with funding from the Department of Science and Technology.

The Minister of Science and Technology, Mr. Derek Hanekom, commented: "This study highlights the importance of international scientific partnerships and the contributions of South African researchers to world-class medical science. The Department of Science and Technology is delighted to have contributed funds for this research. We are proud of the South African research team who conducted this ground-breaking study and thank the US partners for their collaboration and support."

The Minister of Health, Dr. Aaron Motsoaledi, pointed out: "Since South Africa has the largest burden of HIV infection globally, we are gratified to see South African scientists, under Professor Abdool Karim's leadership, undertake this research to find solutions that will bring an end to AIDS. We are hopeful that this research takes us one step closer to developing an AIDS vaccine."

Antibodies in people with HIV that target the virus's gp41 envelope protein can cross-react with normal intestinal bacteria, helping to explain why these antibodies are not effective in controlling HIV infection, according to research published in the August 13 edition of Cell Host & Microbe.